Sunday, April 28, 2013

Giving a speech and need to remember what to say? Just clench your right fist while rehearsing. Then, when it's time to give the speech, clench your left fist, and voila, you’ll recall what you rehearsed! That's what a new study found, which was published April 24 online at PLOS ONE.

Sounds too easy now, doesn't it? And if you're exclaiming, "that's just too good to be true!" — then you'd be correct.

It's true that unilateral hand movement is executed via motor cortex activity in the opposite hemisphere, so the right hemisphere controls the left hand and vice versa.

Such hand clenching is also associated with increased experiencing of a given hemisphere’s “mode of processing.”

This statement is based on EEG studies that have looked at alpha power suppression recorded at scalp electrodes over left and right frontal cortex (Harmon-Jones, 2006). The hypothesis is that left hand contractions "activate" (i.e., suppress alpha waves in) the unhappy right hemisphere, thereby producing negative affect, while right hand contractions activate the happy left hemisphere, which results in positive affect. The affective "modes of processing" aspect of this research isn't directly relevant to the Propper et al. (2013) paper, and further discussion is beyond the scope of this post. I'll just say that attributing EEG activity to a specific cortical region is a dicey proposition, because the spatial resolution of the technique isn't great.1

Together, these findings suggest that unilateral hand clenching can be used to test hypotheses concerning the specializations of the cerebral hemispheres during memory encoding and retrieval.

Here the EEG research on emotion is being applied to memory.

We investigated this possibility by testing effects of unilateral hand clenching on episodic memory. The hemispheric Encoding/Retrieval Asymmetry (HERA) model proposes left prefrontal regions are associated with encoding, and right prefrontal regions with retrieval, of episodic memories.

The Hemispheric Encoding/Retrieval Asymmetry (HERA) model of Tulving et al. (1994) postulates that the left prefrontal cortex encodes information into memory, while the right prefrontal cortex retrieves information from memory. This was back in ye olden days of PET using block designs with 40 seconds of one condition subtracted from 40 seconds of another condition. In other words, poor temporal resolution.

The HERA model was revisited and confirmed by its proponents using fMRI data (Habib et al., 2003), but the evidence against it was considerable (Owen, 2003). The general consensus is that HERA has been discredited. In fact, noted memory researcher Dr. Jon Simons posted a comment at the PLOS ONE website explaining why the underlying hypothesis of Propper et al. is problematic (among other issues).

It was hypothesized that right hand clenching (left hemisphere activation) pre-encoding, and left hand clenching (right hemisphere activation) pre-recall, would result in superior memory.

Here we're expecting to see better memory in the R/L condition than in the control condition. There is no mention that the other fist-clenching conditions would result in worse performance than in the control condition.

Results supported the HERA model.

Results did NOT support the HERA model, and I'll explain why below (and you can read the PLOS ONE comment).

In the experiment, participants studied a list of 36 words, engaged in a filler task, and then recalled as many words as possible. Approximately 10 subjects participated in each of 16 conditions, only five of which are reported in the paper. These involved squeezing a small pink ball in one hand (2 sets of 45 sec) before the encoding and the retrieval phases of the study. The control condition did not involve clenching, but the participants held a small pink ball in each hand.2

The five conditions are shown below, named by the hand used during encoding/retrieval. You'll notice that the number of participants in each group (n) is pretty small. I calculated standard deviations from the standard error values to determine effect sizes using this effect size calculator. 3

Although the authors reported the total number of words written down (correct or not) and the number of correct words in Figs. 1 and 2 respectively, the important result is shown in Fig. 3, which takes into account the false alarms, or incorrectly recalled words.

The one-way ANOVA for this comparison "did not reach traditional significance" (p=.08), but two of the post hoc comparisons did (uncorrected for multiple comparisons involving 16 groups). The p<.09 bar in the figure is in the wrong place. Below is a table I made using the effect size calculator (ESC) for Cohen's d, compared to what was reported in the paper.

The key HERA condition (R/L) did not differ from the control condition, so the predicted hand clenching improvement in memory did not materialize. The superiority of R/L over the other two clenching configurations was due to worse performance in the latter. In other words, if you squeeze a ball with your left hand before encoding, you'll do worse than if you didn't (all statistical objections aside) — and the L clenching before retrieval didn't help. The authors stated otherwise, however:

Individuals who encoded language-based information immediately following right hand clenching (left hemisphere activation), and recalled such information immediately following left hand clenching (right hemisphere activation), demonstrated superior episodic memory compared to the other hand clenching conditions. It is noteworthy that this condition was also superior to the no hand clenching control condition, though not significantly so.

The difference between the two rightmost bars in Fig. 3 above is not terribly close to being significant (as far as I can tell), so the major hypothesis was not supported here.

ADDENDUM #2 (May 5, 2013): There has been a formal correction to Figure 3, which can be downloaded here (as a TIF). This doesn't affect any of the other points I made in this post, which were never addressed.

Footnotes

1 The fist-clenching activation of motor cortex is supposed to spread to dorsolateral prefrontal cortex, or so it goes (Harmon-Jones, 2006).

Friday, April 19, 2013

. . .
From the beginning, the focus of the search for paracetamol’s analgesic mechanism has concentrated on the central nervous system. When administered intraventricularly [i.e., directly into theventricular systemof the brain], acetaminophen produces no significant analgesia (115, 132). This finding lead to attempts to inject acetaminophen into the spinal cord (i.t.), which produced marked dose-related antinociception (132).

Yesterday’s post about Tylenol as a cure for mortality salience and existential dread got me a little worked up. The first author’s public endorsement of acetaminophen as a possible treatment for chronic anxiety disorders was too much to handle (along with the less than stellar experimental rigor). Is watching a 4 min clip of a David Lynch film really the same thing as a clinically diagnosed psychiatric disorder (Randles et al., 2013)? Why Tylenol and not other pain relievers? What is the hypothesized mechanism of action? Wouldn’t we already know by now, from epidemiological studies at the very least, if Tylenol was an effective anti-anxiety medication?

So I started wondering about acetaminophen's actual mechanism of action. I was quite surprised that it's somewhat mysterious. Randles et al. cited one paper on this:

Second, acetaminophen affects a number of brain regions, some of which are not directly related to physical or social distress (Toussaint et al., 2010).

This led me to believe there was evidence from human neuroimaging studies. Turns out there isn't, beyond the Dewall et al. (2010) paper, which states:

Although the precise mechanisms by which acetaminophen exerts an analgesic effect are still unclear, it is widely accepted that acetaminophen reduces pain through central, rather than peripheral, nervous system mechanisms (Anderson, 2008; H.S. Smith, 2009).

I would like to point out that the spinal cord is part of the central nervous system. So if it's really true that acetaminophen exerts its pain-relieving effects through synapses in the spinal cord, then what does this say about providing relief from the angst of social exclusion, mortality salience, and existential dread? That it's based on nociceptive spinal cord neurons in laminae I, II, and V? For a visual illustration of this pathway, I highly recommend viewing the animation, Dissection of DLF blocks analgesia, at Neuroscience Online.

One hypothesis is that Tylenol (acetaminophen) may act on descending serotonergic pathways (purple projection) at the level of the spinal cord (red synapses). Figure modified from Neuroscience Online.

However, it's not that simple. The review paper by Toussaint et al. (2010) concluded, "No one mechanism has been definitively shown to account for its analgesic activity." For its proposed mechanisms of action, they presented evidence both for and against Cyclooxygenase (EC 1.14.99.1, COX) inhibition, COX-1, COX-2, 'COX-3', peroxidase, nitric oxide synthase, cannabinoid receptors, and of course serotonin:

There is substantial evidence that paracetamol’s mechanism of analgesia in some manner involves the descending serotonergical pathway. 5-HT neurons, largely originating in raphe nuclei located in the brain stem (117, 118) send projections down to the spinal cord that synapse on afferent neurons entering the spinal cord. These descending projections exert an inhibitory (analgesic) effect on the incoming pain signal before it is transmited to higher CNS centres.

Note that these are not the same serotonergic pathways often implicated in depression. The terminal synapses for the latter are indeed located in the brain and not the spinal cord.

This morning I dreamt that my workplace had transformed into an institutional fortress taken over by a gang of murderous criminals. The actual law enforcement authorities were too busy watching television talk shows to do anything about it. The thugs were threatening and torturing and killing people in the building. I managed to escape down a balcony exit and hid out for a while, avoiding detection but fearful that the thugs would find me and kill me. They were unstoppable, and there seemed to be no way out. I informed an old West-style sheriff, who managed to detain a carload of the evildoers. While continuing to hide, I wondered whether I would be able to shoot them all dead with a fully automatic weapon before they shot and killed me.

Then an early morning doorbell rang and woke me up. It was an unexpected FedEx delivery. In my barely awake state, I thought it might be a bomb.

Why am I telling you all this?? Because I find it very hard to believe that Tylenol, a drug that's relatively ineffective for my own headache pain, could possibly alleviate the anxiety caused by this nightmare. Or by the real life nightmare that's affected so many people in Boston.

Thursday, April 18, 2013

“In a nameless city, deluged by a continuous rain, three rabbits live with a fearful mystery.”

The latest "elegant and breathtaking"1 paper in Psychological Science presents a rather muddled view of film aesthetics, continental philosophy, surrealism, mortality salience, and stigmatizing attitudes towards sex work (Randles et al., 2013). Oh, and how Tylenol® brand acetaminophen can ease the existential dread evoked by all of these modern horrors.

The authors explained the purpose and implications of their study in the APS press release:

According to lead researcher Daniel Randles and colleagues at the University of British Columbia in Canada, the new findings suggest that Tylenol may have more profound psychological effects than previously thought:

“Pain extends beyond tissue damage and hurt feelings, and includes the distress and existential angst we feel when we’re uncertain or have just experienced something surreal. Regardless of the kind of pain, taking Tylenol seems to inhibit the brain signal that says something is wrong.”

Randles and colleagues knew from previous research that when the richness, order, and meaning in life is threatened — with thoughts of death, for instance — people tend to reassert their basic values as a coping mechanism.

The researchers also knew that both physical and social pain — like bumping your head or being ostracized from friends — can be alleviated with acetaminophen. Randles and colleagues speculated that the existentialist suffering we face with thoughts of death might involve similar brain processes. If so, they asked, would it be possible to reduce that suffering with a simple pain medicine?

No!! I think this is a ridiculous assertion that gets away with using language (and dependent measures) that not only lack precision, but also lack an analogical relation to the real phenomenon under discussion. The leaps of logic were so egregious that I don't know where to begin...

...so let's start with the meaning-maintenance model (MMM) that motivated the work. MMM "posits that any violation of expectations leads to an affective experience that motivates compensatory affirmation" (Randles et al., 2013). Any violation?? So all sorts of psycholinguistics experiments that involve syntactic violations2 will motivate compensatory affirmation? If that's the case, then David Lynch films will often "motivate compensatory affirmation."

But does a David Lynch film “hurt” you?

...Lynch’s films have the ability to “disturb, offend or mystify” (Rodley, 2005, p. 245). Insofar as it “hurts” to watch some of Lynch’s films, as it arguably hurts whenever one is assaulted by thoughts and experiences that are at odds with one’s expectations and values, the question arises as to how this uncomfortable feeling is represented in the brain.

First, David Lynch is one of my favorite directors, and I have never felt "hurt" by watching one of his films. Second, Randles et al.never, at any point in their experiments, address how Lynch-viewing is represented in the brain.

What did the authors actually do? In brief, they asked ~350 young Vancouverites to participate in one of two experiments. In the first study, 121 subjects wrote about death or about dental pain. In the second study, 228 subjects watched a 4 min clip from Rabbits or from The Simpsons. In each case, half of the participants received acetaminophen, half received placebo. Why? What motivated the choice of acetaminophen, as opposed to aspirin, ibuprofen, or naproxen? This was based on a study by Dewall et al. (2010), another problematic paper3 in Psych Sci. There was no mechanistic reason for the original choice.

The present research is predicated on four key findings in the literature: (a) Both physical and social pain are associated with activation in the dACC [dorsal anterior cingulate cortex]4 (e.g., Eisenberger et al., 2003), (b) the dACC is activated in response to anomalies (e.g., Botvinick et al., 2004), (c) social rejection can produce the same compensatory affirmation as other meaning threats (e.g., Nash et al., 2011), and (d) acetaminophen has been shown to reduce physical and social pain, as well as activation in the dACC (DeWall et al., 2010). These findings led us to predict that acetaminophen may also inhibit compensatory affirmation following meaning threats.

The acetaminophen group in Dewall et al. (dose of 2,000 mg a day for 3 weeks) did show less dACC activity in response to cyberball exclusion, but they did not report lower hurt feelings in that situation. The treatment administered by Randles et al. was quite different: a single acute dose of 1,000 mg Tylenol-brand acetaminophen (Rapid Release formula) or 1,000 mg sugar placebo, given 30 min before the critical manipulation.

In Exp. 1, writing two paragraphs about what will happen to your body after death was designed to trigger mortality salience, or thoughts about the inevitability of death. This in turn would lead to compensatory affirmation of cultural views. How was this measured? By assessing the severity of punitive attitudes towards women who engage in sex work! This is the worst part of the study, in my opinion.

Social judgment survey

Finally, participants read a hypothetical arrest report about a prostitute and were asked to set the amount of the bail (on a scale from $0 to $999). This measure has been used in a number of other meaning-threat studies (Proulx & Heine, 2008; Proulx et al., 2010; Randles et al., 2011; Rosenblatt, Greenberg, Solomon, Pyszczynski, & Lyon, 1989). Participants are expected to increase the bond amount after experiencing a threat, because trading sex for money is both at odds with commonly held cultural views of relationships and against the law. Increasing the bond assessment provides participants n opportunity to affirm their belief that prostitution is wrong.

In Canada, the buying and selling of sexual services are legal, but most surrounding activities, such as public communication for the purpose of prostitution, brothels and procuring are offences under the law.

The views of Canadians on prostitution vary greatly according to age and gender, with a large proportion of men and older respondents voicing support for some kind of decriminalization, while most women and younger respondents are not as comfortable with the idea...
. . .

As evidenced in surveys conducted by Angus Reid Public Opinion in 2009 and 2010, only about a quarter of Canadians (22%) are aware that exchanging sex for money is legal in Canada, while seven-in-ten (70%) mistakenly believe that the practice is illegal.
. . .

Still, there is no clear consensus on how some of these guidelines are currently applied. While 36 per cent of respondents believe the Criminal Code provisions related to communication and brothels are fair to the purpose of protecting the public good, almost half (47%) think the rules are unfair and force prostitutes into unsafe situations.

Here are my reactions to the Prostitute-Bail dependent measure:

(1) Yay! Let's stigmatize the prostitute, not the johns!

(2) Does the baseline for these bail judgments differ by sex? age? religion? ethnicity? As professional polling can attest, attitudes vary greatly along demographic lines. The participant pool was quite diverse, and we know nothing about age.

We recruited 121 participants (81 women, 40 men). The sample was predominantly of East Asian (45%), European (29%), and South Asian (12%) descent.

(3) Participants were randomly assigned to one of four groups, but we don't know anything about the randomization - perhaps the most religious and judgmental people ended up in the mortality salience/placebo condition.

(4) To reiterate, we don't know anything about possible demographic differences in the amount of bail set. And that is the only dependent measure!! We don't know how anyone would allocate money or set a price in another situation that is not "morally laden". Let's say you're selling a used car - what would you charge?

At any rate, the authors reported that the mortality-salience/placebo group punished the "norm violator" by a significantly larger amount than the other three groups, t(112) = 2.33, p = .02, d = 0.52.

Fig. 1 (Randles et al., 2013). Results from Study 1: mean bond value set for the prostitute as a function of group (mortality-salience vs. control condition crossed with placebo vs. acetaminophen condition). The scale ranged from $0 to $999. Error bars represent the standard error for each group.

Moving right along to Exp. 2, we discover that the authors decided to use a different dependent measure for no clearly motivated reason. This makes it impossible to compare the outcome of the salience mortality manipulation to the David Lynch manipulation.

We also changed the dependent measure [in Exp. 2]. This study was conducted 3 to 6 months after a well-publicized local riot that followed the Vancouver Canucks’ loss in their bid for the Stanley Cup, and we expected that most students held a negative view of the riot. Thus, we expected that after a threat, participants would affirm this view by calling for stronger punishment for the rioters. Participants were informed that people were debating whether the rioters should be given sentences more lenient than those for comparable individual acts of vandalism, because the rioters had acted impulsively, or should be given stiffer sentences, because they had taken advantage of the city while it was vulnerable. Participants then marked a spot on a line from 0% to 200%. They were told that 0% indicated that rioters should not be fined, that 100% indicated that rioters should receive a normal fine, and that 200% indicated that rioters should receive a doubled fine.

One initial critique is that the Vancouver hockey riot itself provoked MMM. It was a mob event that people could not explain rationally. The subjects were more likely to have been directly affected by this event (in comparison to the hypothetical sex worker bail), by either knowing someone who participated or who was present, or by witnessing the event live or through social media, or by having a favorite business vandalized. In addition, the assigned fines were relative, not absolute. A 150% fine out of... $100 or $1,000 or $10,000?

At any rate, the authors reported that participants in the Lynch/placebo group wanted to punish the rioters by a significantly larger amount than did participants in the other three groups, t(203) = 2.64 p < .01, d = 0.43.

Fig. 2 (Randles et al., 2013). Results from Study 2: mean preference for the penalty to be given individuals convicted of vandalism or theft during the Vancouver hockey riot as a function of group (threat vs. control condition crossed with placebo vs. acetaminophen condition). The rating scale ranged from 0% (no fine for a conviction), through 100% (a normal fine), to 200% (a doubled penalty).

Collectively, the results were taken as evidence that Tylenol can potentially treat chronic anxiety disorders, a conclusion that filled me with existential dread:

The study demonstrates that existentialist dread is not limited to thinking about death, but might generalize to any scenario that is confusing or surprising — such as an unsettling movie.

“We’re still taken aback that we’ve found that a drug used primarily to alleviate headaches can also make people numb to the worry of thinking about their deaths, or to the uneasiness of watching a surrealist film,” says Randles.

The researchers believe that these studies may have implications for clinical interventions down the road.

“For people who suffer from chronic anxiety, or are overly sensitive to uncertainty, this work may shed some light on what is happening and how their symptoms could be reduced,” Randles concludes.

I have a few final questions for the authors, since this violation of my expectations led to an affective experience that motivated my own compensatory affirmation processes:

Why wasn't the dose adjusted by weight? A 45 kg woman got the same dose as a 90 kg man.

Was physical pain assessed in the subjects pre/post-treatment? No it was not.

Did anyone have a headache or any other physical pain before treatment? We don't know... which would be important to know, since relieving physical pain will make you less cranky and irritable.

Is there a single neuroimaging study that has administered acetaminophen at the dose and time course used here? No.

What is the evidence that acetaminophen affects the hemodynamic response in the same exact dACC region hypothesized to control physical, existential, and social pain?

Has there been a single fMRI study in which subjects have watched Rabbits and Simpsons, counterbalanced in a single session while their brains were scanned?

What is the Rabbits > Simpsons neural activation pattern?

Why wasn't there a measure that the Lynch clip was actually "disturbing" or that the Simpsons clip was enjoyable? Actually, none of the manipulations induced changes in affective state on the PANAS.

To ease my existential dread, it's time to watch Rabbits in its entirety.

At meetings and via email, authors often asked me, “What sort of paper is a good candidate for Psychological Science?” ... And when feeling particularly candid, I might say that the ideal Psychological Science manuscript is difficult to define, but easily recognized — the topic is fundamental to the field, the design is elegant, and the findings are breathtaking.

4 At the risk of sounding like a broken record, the dACC has been associated with a wide array of cognitive and emotional control functions (Posner et al., 2007). In the TYLENOL® post, I said:

The "shared neurobiological systems" [for social and physical pain] are thought to be located in the dorsal anterior cingulate cortex (ACC), a brain structure that contains discrete regions responsive to physical pain (Kwan et al., 2000). Interestingly, externally applied vs. self-administered thermal pain activate anatomically distinct areas of the ACC (Mohr et al., 2005). Furthermore, it is not at all clear whether the same regions of ACC represent social pain and the affective components of physical pain. In a study designed to dissociate expectancy violations from social rejection, the dorsal ACC was activated when expectations were violated, while ventral ACC (quite distant from the physical pain regions) was activated by social rejection (Somerville et al., 2006).

The goal of neuroscience is to discover the relationships between brain, behavior, and disease. Using the Brain Systems, Connections, Associations, and Network Relationships (brainSCANr) engine, you can explore the relationships between neuroscience terms in peer reviewed publications.

About Me

Born in West Virginia in 1980, The Neurocritic embarked upon a roadtrip across America at the age of thirteen with his mother. She abandoned him when they reached San Francisco and The Neurocritic descended into a spiral of drug abuse and prostitution. At fifteen, The Neurocritic's psychiatrist encouraged him to start writing as a form of therapy.